Our most recent work on this project has made use of two measures of memory, both involving objects. One type of memory, known as paired associate learning, involves the arbitrary association between two different visual stimuli. A second measure of memory involves the arbitrary association between visual stimuli and spatially-directed responses, known as visuomotor conditional learning. Amnesic patients are notoriously poor in acquiring arbitrary associations, and so these kinds of behavior serve as reliable indicators of memory function. In visuomotor conditional learning, subjects are presented with one of three images on a touch screen and learn which one of three identical target boxes is correct on that trial. The target boxes appear in fixed locations. If the subject chooses the correct location cued by the image for that trial, a reward is delivered. In essence, the subjects learn that each image is associated with a particular spatially directed goal or response. Subjects learn three problems at a time in sessions with novel stimuli, called novel sessions, which because they use new stimuli require the formation of new associative memories. In addition, behavior can be compared for familiar memories, which use well learned stimuli. These sessions are called familiar sessions. In paired associate learning, subjects see images in the same way as in the visuomotor conditional learning. The difference is that they choose a target image associated with it rather than a target box in a fixed location. As in visuomotor conditional learning, behavior on novel and familiar sessions can be contrasted. There is evidence that the hippocampal system is not necessary for paired associate learning. Murray et al. (1993) found that paired associate learning was unaffected by complete removal of the hippocampus. This could mean that the hippocampal system is unnecessary for associative learning when neither component of the association has a relevant spatial attribute. But recent work on this project appears to rule out that account (Brasted et al., 2002, 2003, 2005). This research showed that hippocampal-system damage, specifically a transection of the fornix, impaired fast learning of visuomotor conditional associations even when both the visual stimuli and the responses were nonspatially differentiated. This finding points to another possibility for the results described by Murray et al. (1993). According to this explanation of our paired associate learning results, there was no deficit because subjects learned the paired associates slowly in that prior study. This hypothesis predicts that hippocampal-system damage might cause deficits in the fast learning of paired associates. Accordingly, we are engaged in testing the role of the hippocampus in paired associate learning using a fast learning procedure. This research tests a more general theory of hippocampal function, which holds that it subserves rapid acquisition, as a pattern-associator network, whereas the neocortex acquires similar information, but more slowly. In the context of paired associate learning, this theory implies that the perirhinal cortex, a neocortical area, subserves the slower form of learning and that the hippocampal system subserves the faster form. We have now developed procedures that allow subjects to acquire both visuomotor conditional and paired associations rapidly, within a single testing session. The results from this project could resolve crucial issues about hippocampal and perirhinal cortex function. A second aim of this project is to determine what part of the hippocampal system is essential for fast visuomotor conditional learning. To determine the role of the hippocampus in this task, we assessed the effects on behavior of bilateral infusions into the hippocampus of a neural inhibitor or saline. Our data indicate that there is no effect of hippocampal inactivation on visuomotor conditional learning relative to saline infusion or no infusion. For both novel and familiar sessions, hippocampal inactivation did not impair the overall performance or the rate of learning across blocks of trials. These findings suggest that regions outside the hippocampus proper, either alone or together with the hippocampus, contribute to performance on this task. Candidates include the subicular complex and the entorhinal cortex. Accordingly, we assessed the contribution to visuomotor conditional learning and performance of one other structure in the MTL, the entorhinal cortex. The entorhinal cortex is not only a major source of inputs to the hippocampus, but also has widespread projections to other cortical fields implicated in memory, including the medial prefrontal cortex. Bilateral inactivation of the entorhinal cortex impaired performance on both familiar and novel sessions, and slowed the within-session learning rate during novel sessions. A future aim of this project is to examine the role of MTL-prefrontal interactions in fast associative learning. We predict that both direct and indirect prefrontal-hippocampal connections, via the fornix and entorhinal cortex, respectively, are critical for rapid, arbitrary associative learning of both types studied in this project. If confirmed, this hypothesis could promote the development of therapeutic interventions aimed as facilitating one pathway when damage or disease disrupts the other.